Arginyltransferase suppresses cell tumorigenic potential and inversely correlates with metastases in human cancers

Abstract

Arginylation is an emerging posttranslational modification mediated by arginyltransferase (ATE1) that is essential for mammalian embryogenesis and regulation of the cytoskeleton. Here, we discovered that Ate1 knockout embryonic fibroblasts exhibit tumorigenic properties, including abnormally rapid contact-independent growth, reduced ability to form cell-cell contacts, and chromosomal aberrations. Ate1 knockout fibroblasts can form large colonies in Matrigel and exhibit invasive behavior, unlike wild type fibroblasts. Furthermore, Ate1 knockout cells form tumors in subcutaneous xenograft assays in immunocompromised mice. Abnormal growth in these cells can be partially rescued by reintroduction of stably expressed specific Ate1 isoforms, which also reduce the ability of these cells to form tumors. Tumor array studies and bioinformatics analysis show that Ate1 is down-regulated in several types of human cancer samples at the protein level, and that its transcription level inversely correlates with metastatic progression and patient survival. We conclude that Ate1 knockout results in carcinogenic transformation of cultured fibroblasts, suggesting that in addition to its previously known activities Ate1 gene is essential for tumor suppression and also likely participates in suppression of metastatic growth.

Multiple competing RNA structures dynamically control alternative splicing in human ATE1 gene

“…There was almost no evidence of simultaneous inclusion or simultaneous skip of both exons neither in normal tissues ( Figure S1A), nor in cancer samples from The Cancer Genome Atlas ( Figure S1B) (35). However, in agreement with previous studies (16), we detected a significant prevalence of isoforms containing exon 7b as compared to exon 7a in matched samples of prostate adenocarcinomas and normal tissues (FWER<0.05) and also in other epithelial tumors including stomach, rectum, colon, and lung squamous cell carcinoma ( Figure 1C).…”

“…Ate1 is essential in most eukaryotic systems and is implicated in regulation of many physiological pathways including proteolysis (3,4), response to stress and heat shock (5)(6)(7), embryogenesis (8)(9)(10), regenerative processes (11)(12)(13), and aging (14,15). Ate1 has recently been identified as a master regulator affecting disease-associated pathways (16)(17)(18), and its knockout results in embryonic lethality and severe developmental defects in mice (9,10,19,20).…”

Post‐translational protein arginylation in the normal nervous system and in neurodegeneration

“…A recent study showed that fibroblasts derived from ATE1 knockout mice have contact inhibition defects that are associated with tumorigenic transformation; suggesting that ATE1 acts as a tumor suppressor factor whose expression level may serve as a biomarker for metastasis (Rai et al . ).…”

“…The effect of ATE1 activity on nuclear action of MRTF-A was not elucidated at the molecular level; however, these findings illustrate the global impact of protein arginylation on processes such as cell motility. A recent study showed that fibroblasts derived from ATE1 knockout mice have contact inhibition defects that are associated with tumorigenic transformation; suggesting that ATE1 acts as a tumor suppressor factor whose expression level may serve as a biomarker for metastasis (Rai et al 2015).…”

Protein arginylation regulates cellular stress response by stabilizing HSP70 and HSP40 transcripts

“… 11 A large variety of proteins identified as target for arginylation shown to regulate many of the cell’s function, including cell migration, cell proliferation, tumorigenesis, apoptosis, actin cytoskeletal dynamics, cell-to-cell adhesion, purine metabolism, G-protein signaling, oxidative stress sensing, and stress response. 2 , 12–20 Among these stress response is focus of the current investigation.…”